The emergence of multidrug resistant (MDR) bacterial pathogens (e.g. methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii-calcoaceticus complex (ABC), etc.) has added increasing concerns as to the adequacy of current antimicrobials and pathogen treatment methods. The lethality of such pathogens, particularly MRSA, has often led to treatment methods that are experimental or would otherwise normally be avoided in standard clinical practice. For example, the antibiotic colistin was traditionally considered too nephrotoxic and neurotoxic for clinical use, but is nevertheless used to treat many MDR bacterial infections due to a paucity of available active drugs. The growing threat from MDR pathogens highlights a critical need to expand currently available antimicrobials. In this connection, new antibiotics must be developed that exhibit novel mechanisms of action as well as the ability to circumvent known resistance pathways.
Elements of the bacterial cell division machinery present appealing targets for antimicrobial compounds because (i) they are essential for bacterial viability, (ii) they are widely conserved among bacterial pathogens, and (iii) they often have markedly different structures than their eukaryotic homologs. One such protein that has been identified as a potential target is the FtsZ protein. During the division process, FtsZ, along with approximately 15 other proteins, assemble at mid-cell into a large cell division complex (termed the divisome), ultimately facilitating cell cytokinesis. More importantly, FtsZ is widely conserved among many bacterial strains.
The appeal of FtsZ as a target has led to the identification of several FtsZ-directed inhibitors. Benzo[c]phenanthridines (e.g. sanguinarine and chelerythrine) present an emerging class of such inhibitors (Beuria, T. K., et al., Biochemistry 44:16584-16593). More specifically, benzo[c]phenanthridines (B[c]P compounds) prevent GTPase activity and FtsZ polymerization by competitively inhibiting the binding of GTP to FtsZ. Such competitive inhibition prevents FtsZ Z-ring formation and, ultimately, bacterial cell cytokinesis. Thus, these compounds are effective as antimicrobials.
Given the lethality of many MDR pathogens, an antimicrobial with heightened competitive inhibition of FtsZ GTPase activity is desirable. More specifically, an antimicrobial is desirable that increases the competitive inhibition of GTP binding to the FtsZ protein so as to effectively prevent FtsZ polymerization, FtsZ Z-ring formation, and bacterial cell division.
The present invention address one or more of the foregoing needs.